CN104447479A - Derivative containing adamantane and amides and preparation method and application thereof - Google Patents
Derivative containing adamantane and amides and preparation method and application thereof Download PDFInfo
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- CN104447479A CN104447479A CN201510016778.6A CN201510016778A CN104447479A CN 104447479 A CN104447479 A CN 104447479A CN 201510016778 A CN201510016778 A CN 201510016778A CN 104447479 A CN104447479 A CN 104447479A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to the field of drugs relevant to diabetes, in particular to a dipeptidyl peptidase-IV inhibitor containing a general formula I, adamantane, amide and other structures, a preparation method of the dipeptidyl peptidase-IV inhibitor and application in diabetes drug preparation. According to the general formula I (please see the specification), R<1> is selected from an alkyl group of H, an alkyl group of C1-C5 and a naphthenic base of C3-C5.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes.Specifically, the present invention relates to diabetes medicative containing diamantane and the isostructural dipeptidyl peptidase-iv inhibitor of acid amides and preparation method thereof, containing they pharmaceutical composition and treatment diabetes in medicine.
Background technology
According to statistics, global diabetic subject nearly about 2.5 hundred million in 2007, wherein large absolutely number is II type (i.e. non-insulin-depending type) diabetic subject.Mainly contain sulfonylurea, N1,N1-Dimethylbiguanide class and trypsin class medicine at the antidiabetic medicine of Clinical practice at present, what go on the market in recent years also has medicament of insulin sensitizer and alpha-glucosidase inhibitor etc.These medicines have good therapeutic action, but the serious side effects such as ubiquity hypoglycemia, and there is safety issue in long-term treatment, as problems such as liver toxicity and body weight increases.
DPP IV (dipeptidyl peptidase IV, DPP-IV) can effectively and to degrade rapidly glucagon-like peptide 1 (GLP-1), GLP-1 is one of insulin production and the most effective stimulant of secretion, therefore suppress DPP-IV can strengthen the effect of endogenous GLP-1, thus improve the level (CN200480017355.6) of Regular Insulin in blood.Current medical science has confirmed that DPP-IV inhibitor is a kind of novel antidiabetic treatment medicine, has had multiple medicine list marketing at present.Clinical effectiveness shows such medicine and has good hypoglycemic effect, does not find the untoward reaction thing such as the common body weight increase that other diabetes medicaments produce and hypoglycemia simultaneously.
The major structural types of existing DPP-IV inhibitor has: chemically structure type divides and is mainly divided into piperazine and triazole species, 2-cyano-pyrolidin class, thiazolidines, Pyrimdinone, and other types structure medicament.
The invention discloses a class containing diamantane and the isostructural DPP-IV inhibitor of acid amides, these compounds may be used for the medicine preparing treatment diabetes.
Summary of the invention
An object of the present invention is to provide one and there is excellent activity, there is compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for salt thereof.
Another object of the present invention is to provide the application of compound in treatment diabetes containing general formula I.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R
1be selected from the alkyl of H, C1-C3, the cycloalkyl of C3-C5.
The compound that preferred the present invention has general formula I is as shown in the table:
Compound of Formula I of the present invention is synthesized by following steps:
Compound II per reacts with III under condensing agent exists, and obtains compound IV; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains V; Compound V reacts with VI under condensing agent exists, and obtains compound VI I; Compound VI I acid treatment is sloughed Boc protecting group and is obtained I.
Above-mentioned condensing agent comprises N, N'-dicyclohexyl carbodiimide (DCC), N-ethyl-N'-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDC) and carbonyl dimidazoles (CDI) etc., these condensing agents can with organic bases conbined usage, as triethylamine, diisopropyl ethyl amine (DIPEA) and DMAP (DMAP) etc.The condition of above-mentioned catalytic hydrogenolysis comprises and using such as Pd/C and Pd (OH)
2deng catalyzer, hydrogen source comprises hydrogen, HCO
2h, HCO
2nH
4with tetrahydrobenzene etc.Above-mentioned acid comprises hydrochloric acid, sulfuric acid, methylsulfonic acid, trifluoroacetic acid and tosic acid etc.
Wherein, R
1definition as previously mentioned.
The pharmacy acceptable salt of formula I of the present invention comprises, but be not limited to and various mineral acid, such as, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, the pharmacy acceptable salt that such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid etc. generate.
Compound or its salt shown in formula I has the restraining effect of DPP-IV, can be used as effective constituent for the preparation of in treatment diabetes medicament; Preferably, described diabetes are non insulin dependent diabetes.The activity of the compounds of this invention is verified by the external restraining effect to DPP-IV enzyme.
Compound of Formula I of the present invention or its salt have the restraining effect of DPP-IV, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in body.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
The preparation of embodiment 1 Compound I-1
2.22g (10mmol) Compound II per-1,3.21g (10mmol) compound III, 2.06g (10mmol) N is added in the round-bottomed flask of a 100mL, N'-dicyclohexyl carbodiimide (DCC) and 1.22g (10mmol) DMAP (DMAP), dissolve with the THF of 20mL drying, room temperature for overnight, TLC display reaction completes substantially.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=543 ([M+NH
4]
+).
3.15g (6mmol) compound IV-1 is dissolved in 30mL THF, adds 0.10g 10%Pd/C, and catalytic hydrogenolysis under room temperature is reacted and completed in 12 hours.Reaction mixture suction filtration removing catalyzer, filtrate pours in 200mL water after concentrating on a rotary evaporator, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain V-1 sterling, white solid, ESI-MS, m/z=434 ([M-H]
-).
1.74g (4mmol) compound V-1,0.38g (4mmol) compound VI, 0.82g (4mmol) DCC and 0.49g (10mmol) DMAP (DMAP) stir and spend the night in the THF of 15mL drying.Reaction mixture suction filtration removing solid, filtrate is evaporate to dryness on a rotary evaporator, and resistates column chromatography purification, obtains compound VI I-1, white solid, ESI-MS, m/z=531 ([M+NH
4]
+).
1.03g (2mmol) compound VI I-1 is dissolved in the mixed solvent of 1mL methylene dichloride and 1mL trifluoroacetic acid, room temperature for overnight.Reaction mixture is poured in 100mL frozen water, stirs, with 50mL × 3 dichloromethane extraction.Merge extraction phase, with brine It, anhydrous sodium sulfate drying, on a rotary evaporator evaporate to dryness, resistates column chromatography purification, obtain I-1 sterling, white solid, ESI-MS, m/z=431 ([M+NH
4]
+).
Embodiment 2-6
With reference to the method for embodiment 1, following compounds can be prepared.
Embodiment 7 compound measures the restraining effect of DPP-IV enzyme
Use the fluorescence DPP4 activity detection kit of BPS Biological Science Co., Ltd, measure the inhibit activities of compound of the present invention to DPP-IV enzyme.
Be respectively by gradient dilution concentration successively by sample: 5,10,30,100 and 200ng/kg, fluorescent reaction 96 orifice plate, according to the form below adds sample:
22 DEG C of water-baths, place 10min, Spectra Max M5 type fluorimetric detector exciting light 350nm, with 450nm fluorometric assay absorption value.IC is calculated according to concentration-fluorescence intensity curves
50value, the results are shown in following table.
Compound is to the IC of the suppression of DPP-IV enzyme
50value
As can be seen from the above table, compound of the present invention has very strong restraining effect to DPP-IV enzyme.
Claims (4)
1. there is compound or its pharmacy acceptable salt of general formula I:
Wherein, R
1be selected from the alkyl of H, C1-C3, the cycloalkyl of C3-C5.
2. the compound of Formula I that defines of claim 1 or its pharmacy acceptable salt, is selected from:
3. synthesize the method for the compound of Formula I that defines of claim 1-2 or its pharmacy acceptable salt:
Compound II per reacts with III under condensing agent exists, and obtains compound IV; Compound IV uses the method for catalytic hydrogenolysis to slough Bn protecting group and obtains V; Compound V reacts with VI under condensing agent exists, and obtains compound VI I; Compound VI I acid treatment is sloughed Boc protecting group and is obtained I; Wherein, R
1definition as arbitrary in claim 1-3 shown in.
4. the compound of Formula I that defines of claim 1-2 or the application of its pharmacy acceptable salt in preparation treatment diabetes medicament.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510016778.6A CN104447479B (en) | 2015-01-13 | 2015-01-13 | Containing diamantane and amide derivatives, Preparation Method And The Use |
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|---|---|---|---|
| CN201510016778.6A CN104447479B (en) | 2015-01-13 | 2015-01-13 | Containing diamantane and amide derivatives, Preparation Method And The Use |
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| CN104447479A true CN104447479A (en) | 2015-03-25 |
| CN104447479B CN104447479B (en) | 2016-03-23 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058849A1 (en) * | 2003-12-15 | 2005-06-30 | Glenmark Pharmaceuticals Ltd. | New dipeptidyl peptidase in inhibitors; process for their preparation and compositions containing them |
| WO2005073186A1 (en) * | 2004-01-29 | 2005-08-11 | Ono Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| EP2006284A1 (en) * | 2006-04-05 | 2008-12-24 | Shanghai Hengrui Pharmaceutical Co. Ltd. | Dicyclooctane derivates, preparation processes and medical uses thereof |
| CN101970402A (en) * | 2008-03-05 | 2011-02-09 | 财团法人国家卫生研究院 | Pyrrolidine derivatives |
-
2015
- 2015-01-13 CN CN201510016778.6A patent/CN104447479B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005058849A1 (en) * | 2003-12-15 | 2005-06-30 | Glenmark Pharmaceuticals Ltd. | New dipeptidyl peptidase in inhibitors; process for their preparation and compositions containing them |
| WO2005073186A1 (en) * | 2004-01-29 | 2005-08-11 | Ono Pharmaceutical Co., Ltd. | Pyrrolidine derivatives |
| WO2006012441A1 (en) * | 2004-07-23 | 2006-02-02 | Susan Marie Royalty | Peptidase inhibitors |
| EP2006284A1 (en) * | 2006-04-05 | 2008-12-24 | Shanghai Hengrui Pharmaceutical Co. Ltd. | Dicyclooctane derivates, preparation processes and medical uses thereof |
| CN101970402A (en) * | 2008-03-05 | 2011-02-09 | 财团法人国家卫生研究院 | Pyrrolidine derivatives |
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| CN104447479B (en) | 2016-03-23 |
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Denomination of invention: Derivative containing adamantane and amides and preparation method and application thereof Effective date of registration: 20170816 Granted publication date: 20160323 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
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Date of cancellation: 20190604 Granted publication date: 20160323 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
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Effective date of registration: 20190716 Address after: 038300 Jinshatan Medical Park, Huairen County, Shuozhou City, Shanxi Province Patentee after: Huairen Chenglong Chemical Technology Co., Ltd. Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
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